1. Field of the Invention
The invention relates to methods and pharmaceutical compositions used to prevent kidney toxicity caused by cyclosporin or tacrolimus administration.
2. Description of the Prior Art
Cyclosporins are neutral, lipophilic, cyclic undecapeptides with molecular weights of about 1200. They are used intravenously or orally as immunosuppressants to prolong survival in allogenic transplants involving skin, bone marrow, heart, kidney, pancreas and other organs as well as in the treatment of autoimmune diseases.
One of the principal categories of adverse reactions experienced with cyclosporin therapy is renal dysfunction and toxicity, which creates limitations on the clinical applications of cyclosporins. Indeed, in spite of improved one- and two-year renal allograft survival rates, the average half-life of eight years for a cadaver kidney transplant that is functioning at one year has changed little with the use of cyclosporin-based immunosuppression during the past over 15 years. The adverse effects of cyclosporins, particularly the most commonly used cyclosporin, cyclosporin A (CyA) on long-term kidney structure and function have not been excluded as an important factor in chronic allograft failure syndrome. See Bennett et al., Kidney Intl. , 50:1089-1100 (1996).
It has been established that CyA causes a dose-related decrease in renal function in experimental animals and humans which is thought to be due to the drug's effects in producing afferent arteriolar vasoconstriction and, ultimately, decreased glomerular filtration rate. However, these acute hemodynamic effects, which should be largely controllable with precise monitoring and dosing of patients, are apparently not the only adverse consequences of CyA administration for the kidney. Not only patients given CyA therapy to prevent organ transplant rejection, but also patients with autoimmune diseases, have been shown to develop morphologic lesions consisting of areas of striped tubulointerstitial fibrosis, tubular atrophy and afferent arteriolopathy. The hallmark of CyA nephropathy are these vascular lesions, which are not necessarily dose-related and which can be observed in some patients receiving CyA doses as low as 2 to 4 mg/kg. See Bennett et al., ibid.; Pankewycz et al., Kidney Intl., 50:1634-1640 (1996).
No effective technique has been disclosed in the prior art for the chronic administration of CyA and other cyclosporins at therapeutic doses while avoiding the serious consequences of nephrotoxicity. It has been suggested that calcium antagonists may modify the metabolism of CyA, allowing the use of lower doses to achieve adequate immunosuppression. It has also been proposed that dihydropyridine calcium channel blockers may slow interstitial fibrosis in kidney transplant recipients without affecting cyclosporin metabolism. The benefit of these proposed therapies has not been established, however, and there may be adverse effects caused by the chronic administration of calcium antagonists or calcium channel blockers that would outweigh their utility as adjunctive agents to cyclosporins even if they were effective in avoiding kidney damage.